Pulmonary fibrosis, the progressive and irreversible replacement of normal lung parenchyma with fibrotic tissues, is a major clinical burden when organ function is compromised. Treatment options for this disease are severely limited, underscoring the urgent need for therapies to attenuate and/or halt disease progression before organ failure. Characteristic features of pulmonary fibrosis include focal expansion of fibroblasts and deposition of extracellular matrix, and activated fibroblasts are key executors of this process. TGF is well known as a potent pro-fibrogenic cytokine driving lung fibrogenesis, and TGF exerts much of its effects via interactions with integrins, a family of transmembrane receptors which consist of a and a subunit. Five integrins share the v subunit, including v1, v3, v5, v6, and v8, and all can activate TGF. While expression of v6 is restricted to the epithelium, others are expressed in fibroblasts in multiple organs including lung Epithelium-restricted v6 has been previously shown to spatially activate TGF, and this v6-mediated TGF activation has been demonstrated as an important player during lung fibrogenesis. Compared to v6, the role of other v integrins on fibroblasts in pulmonary fibrosis is less understood. Notably, our lab has recently found that in vivo deletion of v integrins on pericytes/fibroblasts protects mice from fibrosis in several classic models, including bleomycin-induced pulmonary fibrosis, unilateral ureteral obstruction-induced renal tubulointerstitial fibrosis, and carbon tetrachloride-induced hepatic fibrosis, which suggests that v integrins on pericytes/fibroblasts are central mediators during fibrogenesis across solid organs. One goal of this proposed research aims to identify which sub-population of fibroblasts is critical for this v integrin-mediated development of pulmonary fibrosis. Current literature implicates myofibroblasts, the subpopulation of fibroblasts expressing -SMA, as the major activated fibroblasts during fibrogenesis; however, this idea remains controversial, and the specific role of myofibroblasts has not been rigorously investigated in vivo. As such, a mouse line in which myofibroblasts can be specifically targeted and genetically manipulated has been generated for this research, and whether loss of v integrins on myofibroblasts protects mice from bleomycin-induced pulmonary fibrosis will be examined. In addition, by combining cell-type specific reporter mice and cell sorting techniques, the regulatory role of v integrins on activate fibroblasts will be characterized. Finally, by using both genetic and pharmacologic tools, which one or more fibroblast v integrin(s) is/are critical to contribute to pulmonary fibrosis in vivo wll be determined. Overall, this proposed research should define the role of myofibroblasts in vivo during lung fibrogenesis, and may unravel new therapeutic target(s) for the development of anti-fibrotic agents to treat pulmonary fibrosis.